The present invention relates to mammals and cell lines in which the expression of the Fgl-2 gene has been suppressed. The invention also includes constructs that are useful in preparing the mammals and cell lines.
Fulminant viral hepatitis is characterized by the rapid appearance of jaundice, coagulopathy and encephalopathy and reflects severe hepatocellular dysfunction and necrosis. Thrombosis is a common feature of fulminant hepatitis and may occur in viral infections complicated by disseminated intravascular coagulation. Monocytes/macrophages respond to infection with hepatitis viruses by generating procoagulant activity (PCA) and also produce monokines such as TNF and IL-2, which in turn can induce other cells like endothelial cells to produce PCA. Activation of the coagulation pathways is an important part of immune and inflammatory reactions and accounts for the fibrin deposition in these reactions. Furthermore, the inventors have shown that the elaboration of PCA by monocytes/macrophages parallels the susceptibility to fulminant hepatitis caused by murine hepatitis virus strain 3 (MHV-3). As described in applicant""s co-pending application Ser. No. 09/442,143, which is incorporated herein by reference in its entirety, the applicant""s identified the MHV-3 induced procoagulant as a direct prothrombinase Fgl-2 and the mouse and human sequences have been sequenced. Clinical conditions other than hepatitis in which Fgl-2 is implicated include allograft rejection, fetal loss, inflammatory bowel disease lupus glomerulonephritis, acute respiratory disease syndrome, Whipple""s disease, and cancer.
In view of the role of Fgl-2 in various diseases it is useful to prepare an Fgl-2 knockout model in order to further elucidate its function in these diseases and importantly to develop therapies to treat the diseases.
The present inventors have prepared vectors comprising the Fgl-2 gene as well as mammals and cell lines in which the expression of Fgl-2 has been suppressed.
Accordingly, in one aspect, the present invention provides a nucleic acid construct comprising a nucleic acid sequence comprising at least a portion of an Fgl-2 gene linked to a marker sequence.
In another aspect, the present invention provides an embryonic stem cell containing a nucleic add construct of the invention.
In a further aspect, thepresent invention provides a non-human animal and its progeny having decreased expression of the Fgl-2 gene.
In a further aspect, the present invention further provides a method of preparing a non-human animal with decreased expression of an Fgl-2 gene comprising inserting into the genome of the non-human animal a nucleic acid sequence comprising at least a portion of an Fgl-2 gene linked to a marker sequence.
The non-human animals of the present invention are useful in studying Fgl-2 and diseases wherein Fgl-2 is implicated including viral hepatitis, graft rejection, fetal loss syndrome, inflammatory bowel disease, lupus glomerulonephritis, acute respiratory disease syndrome, Whipple""s disease and cancer. The non-human animals are also useful in identifying therapeutic agents that may be useful in treating these conditions.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.